WO1989007890A1

WO1989007890A1 - Antimicrobial agents

Info

Publication number: WO1989007890A1
Application number: PCT/EP1989/000161
Authority: WO
Inventors: Harold A. Brandman; Milton Manowitz; Albert I. Rachlin
Original assignee: L. Givaudan & Cie Societe Anonyme
Priority date: 1988-02-26
Filing date: 1989-02-22
Publication date: 1989-09-08
Also published as: NO177451C; AU635702B2; FI895066A0; DK534089D0; FI91252B; JPH02503319A; DK534089A; NO177451B; DE68915499D1; DE68915499T2; EP0360850A1; NO894254D0; JP2562215B2; EP0360850B1; NO894254L; CA1338896C; AU3188289A; ATE105993T1; FI91252C

Abstract

Useful as antimicrobial agents are beta-substituted alpha-halo-acrylonitriles of formula (I), wherein X represents chlorine, bromine or iodine and R represents a lower alkyl, aryl, aralkyl, heterocyclyl, or thiocarbonyl group. These compounds may be incorporated in aqueous compositions subject to spoilage by microbial growth to control such growth. All the compounds apart from alpha-bromo-beta-methylthio-acrylonitrile and the corresponding beta-phenylthio compound are novel and may be produced (in a final reaction step) by nucleophilic-type displacement of the beta-halogen atom X of an appropriate alpha,beta-dihalo-acrylonitrile X-CH=CX(CN) (IV) using a sulfur anion RS derived from the appropriate mercaptan RSH.

Description

ANTIMICROBIAL AGENTS

A number of aqueous systems are susceptible to microbial growth. Among these are latex paints, soaps, cutting oils, adhesives, cosmetic products, other oil and water emulsions, white water used in paper mills and water recirculated in industrial cooling towers and the like. The growth of bacteria and fungi in such systems can be a serious problem if not properly controlled. There is. consequently, a continuing need to provide effective and economical antimicrobial agents which protect these systems.

The antimicrobial agents of this invention are β-substituted α-halo-acrylonitriles of the formula

I

wherein X represents chlorine, bromine or iodine and R represents a lower alkyl, aryl, aralkyl, heterocyclyl or thiocarbonyl group. The configuration about the double bond may be E or Z or a mixture thereof. These compounds provide effective control of microbial growth.

Accordingly, the present invention provides a method of controlling microbial growth in an aqueous composition subject to spoilage thereby, which comprises incorporating in said composition an effective amount of a compound of the formula I hereinabove. Under the term "lower alkyl" there are to be understood in particular straight or branched chain alkyl groups containing up to 6 carbon atoms, preferably 1 to 4 carbon atoms. The term "aryl" embraces the usual aryl groups, in particular phenyl and naphthyl. which may feature one or more substituents such as halogen, lower alkyl. lower alkoxy. nitro etc. The aryl portion of "aralkyl" is to be similarly interpreted, and the alkyl portion thereof is particularly straight or branched chain C_1-4-alkyl. "Heterocyclyl" embraces a large range of such groups which feature inter alia one or more of oxygen, sulphur and nitrogen atoms as the ring heteroatom(s) and, optionally, one or more ring carbonyls and/or fused benzene rings. The heterocyclic ring may be aromatic in character or at least partially saturated. Finally, under the term "thiocarbonyl group" there are to be understood acyl groups derived from dithiocarboxylic acids by removal of the SH moiety therefrom. Suitable dithiocarboxylic acids include dithioformic acid, dithioacetic acid and further lower dithioalkanoic acids, dithiocarbamic acid, dimethyldithiocarbamic acid and further di(lower alkyl)-dithiocarbamic acids. The thiocarbonyl group can thus be inter alia thioacetyl. thiocarbamoyl or dimethylthiocarbamoyl.

In the formula I R is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. butyl, isobutyl or tert. butyl; phenyl or p-chlorophenyl; benzyl; 2-thiazolyl or 2-benzothiazolyl; or thioacetyl, thiocarbamoyl or dimethylthiocarbamoyl. Independently, X is preferably chlorine or bromine, especially the former halogen. Particularly preferred individual compounds of formula I are:

α-Chloro-β-methylthio-acrylonitrile, α-chloro-β-ethylthio-acrylonitrile, α-bromo-β-methylthio-acrylonitrile and α-bromo-β-ethylthio-acrylonitrile. The derivatives of formula I are economically prepared from acrylonitrile (a readily available monomer widely used in the manufacture of plastics and polymers) via a three-step process involving (a) halogenation. (b) dehydrohalogenation and (c) nucleophilic-type displacement as illustrated below.

/

Acrylonitrile (II) is converted to the corresponding α,α,β-trihalopropionitrile (III) by reaction with an appropriate halogenating agent such as elemental chlorine, bromine or iodine, using methods known in the art [see for example, J G. Lichty. U.S. P. 2,231.838, February 11, 1941]. The resultant trihalo derivative (III) is converted to the corresponding α,β-dihaloacrylonitrile (IV) via a dehydrohalogenation reaction using inorganic or organic alkaline reagents or other methods known in the art [see for example. A.N. Kurtz et al., J. Org. Chem. 3J). 3141-47 (1965)]. Displacement of the halogen atom attached to the β-carbon can be accomplished using a nucleophilic sulfur anion derived from an appropriate mercaptan to yield the desired β-substituted α-halo-acrylonitrile (I). The methods, techniques and reagents used are similar to those known in the art [see for example. B. Miller et al.. Tetrahedron 23, 1145-52 (1967)]. The acrylonitriles of formula I exist as a mixture of the E-and Z-isomers. Except for α-bromo- -β-methylthio-acrylohitrile and α-bromo-β-phenylthio--acrylonitrile, the compounds of formula I are not mentioned in the literature and form a further object of the present invention. Furthermore, the present invention provides the process for producing the novel compounds of formula I comprising subjecting the α,β-dihaloacrylonitrile (IV) to a nucleophilic-type displacement of the halogen atom attached to the β-carbon atom using a sulfur anion RS^Θ derived from the appropriate mercaptan RSH.

As illustrated above the compounds of formula I may be prepared by reaction of acrylonitrile with a halogenating agent such as elemental chlorine, bromine or iodine to yield the α,α,β-trihalopropionitrile (III). The halogenation reaction may be run with or without a solvent. If a solvent is used, it must be chosen from those solvents which are inert towards and do not react in any way with the halogenating agents. Such solvents would include but not be limited to ether, carbon tetrachloride, chloroform. methylene chloride and ethylene dichloride. For economical reasons it is preferred not to use a solvent.

The halogenation reaction may be carried out at 0-80°C. Normally the reaction temperature is controlled by the boiling points of acrylonitrile (77°C), the halogenating agent and/or the reaction solvent if a solvent is used. A reaction temperature of 10-50°C is preferred, with a reaction temperature of 25-35°C being especially preferred.

For economical considerations chlorine and bromine are the preferred halogenating agents. Chlorine is especially preferred due to its lower molecular weight (i.e., 71 g/mole for chlorine as opposed to 159.8 g/mole for bromine and 253.8 g/mole for iodine), lower price, availability and greater ease in handling. The α,α,β-trihalopropionitrile (III) is converted to the corresponding α,β-dihaloacrylonitrile (IV) via a dehydrohalogenation reaction using an appropriate base. The base may be chosen from organic bases such as primary, secondary or tertiary aliphatic amines, alicyclic amines, or heterocyclic bases such as pyridine, lutidine, quinoline, etc. The base may also be chosen from inorganic bases such as alkali metal carbonates or hydroxides. It is preferred to use an organic base due to their greater miscibility with the α,α,β-trihalopropionitrile derivatives. Heterocyclic bases such as lutidine or quinoline are especially preferred.

It is preferred to carry out the dehydrohalogenation step using an organic base in the absence of a solvent. The reaction gives rise to the formation of an insoluble amine hydrohalide salt as a by-product, which is easily removed by filtration at the end of the reaction. If the use of a solvent is desired the solvent should be one which is not acidic or reactive with the organic or inorganic base being used to effect the dehydrohalogenation, and should be somewhat non-polar so as to render the by-product salt insoluble in the reaction medium. Such solvents would include but not be limited to ether, hexane, heptane, benzene, toluene, xylene, carbon tetrachloride, etc. It is especially preferred not to use a solvent since it simplifies product isolation and purification.

The dehydrohalogenation reaction can be suitably carried out at 20-200°C and is only limited by the boiling points of the starting material (α,α,β-trihalopropionitrile), the product (α,β-dihaloacrylonitrile), the amine used and the solvent if one is used. A reaction temperature of 20-180º is preferred, with a temperature of 40-90°C being especially preferred.

The α,β-dihaloacrylonitrile (IV) can be converted to the corresponding β-substituted α-halo-acrylonitrile (I) via a nucleophilic-type displacement of the halogen atom attached to the β-carbon atom by a sulfur anion derived from the appropriate mercaptan. The sulfur anion is most conveniently prepared in situ by reaction of a mercaptan with a strong base. Representative of mercaptans that can be used are alkyl mercaptans (either straight-chain such as methyl mercaptan. ethyl mercaptan. n-propyl mercaptan. etc., or branched-chain such as isopropyl mercaptan. isobutyl mercaptan, secondary butyl mercaptan, tertiary butyl mercaptan. etc.), aromatic mercaptans (e.g., thiophenol, para-chlorothiophenol), aralkyl mercaptans (e.g., benzyl mercaptan), heterocyclic mercaptans (e.g., 2-mercaptothiazole, 2-mercaptobenzothiazole), and dithiocarboxylic acids (e.g., dithioacetic acid, dithiocarbamic acid). The scope of this invention is not limited to the various mercaptans mentioned above, said list being merely representative of the general nature of the reaction.

The formation of the sulfur anion involves the removal of the acidic hydrogen atom bonded to the sulfur by an inorganic base such as the hydroxyl, alkoxyl, amide or hydride ion. The use of bases such as metal hydroxides or alkoxides involves the transfer of a proton to the conjugate base while the use of metal hydrides or amides involves the irreversible formation of ammonia or hydrogen gas. The use of the latter two bases (i.e., metal hydrides or metal amides) is less favored since they are more expensive, more hazardous and less amenable to large scale industrial processing. The base may also be chosen from organic bases such as primary, secondary or tertiary aliphatic amines

(e.g. triethylamine) or from alicylic amines. The use of metal hydroxides and metal alkoxides are preferred with metal hydroxides, such as sodium hydroxide or potassium hydroxide being most preferred.

The sulfur anion can be prepared by adding the appropriate mercaptan to a solution of the base in an appropriate solvent. The choice of solvent may depend upon the base being used. With metal hydroxides or alkoxides the use of alcoholic solvents such as methanol. ethanol, isopropanol. n-propanol, etc. is desirable. When using metal alkoxides, the alcohol solvent must be anhydrous to prevent hydrolysis of the alkoxide to hydroxide. With metal hydrides and amides the choice of solvents is limited to aprotic, anhydrous solvents, such as ether, glyme, diglyme, tetrahydrofuran. etc. These solvents tend to be more expensive, thereby rendering the use of metal hydrides and amides less attractive for large scale industrial processing.

The α,β-dihaloacrylonitrile (IV) is slowly fed into the solution of the sulfur anion. The displacement reaction may be carried out at temperatures of 0-80°C, the maximum operating temperature being limited by the boiling point of the reaction solvent and the boiling point of the mercaptan being used. Temperatures of 20-50°C are preferred, with the temperatures of 25-35°C being especially preferred.

Those compounds of formula I wherein X is chlorine are preferred in the practice of the present invention. The β-substituted α-chloro-acrylonitriles exemplified herein, including those wherein R is an alkyl, aryl, aralkyl, heterocyclyl or thiocarbonyl group, all show broad spectrum activity toward fungi. Those derivatives wherein R is methyl or ethyl show a broad spectrum of activity against both fungi and bacteria and are especially preferred since they would be suitable for a wider variety of applications. While less preferred than the compounds wherein X is chlorine, the corresponding compounds where in X is bromine show good activity . Those compounds of formula I wherein X is bromine and R is methyl or ethyl show broad base activity against fungi and bacteria. The compounds of formula I wherein X is iodine are also suitable antimicrobial agents. The compounds of formula I may be added to aqueous systems or formulations that are susceptible to bacterial or fungal growth, either undiluted or dissolved in organic solvents such as alcohols, acetone, dimethylformamide and the like. They may be added alone or in combination with other biocides and/or functional compounds such as antioxidants, anticorrosive agents, surfactants, etc. Such compositions of the compound of formula I dissolved in an organic solvent are also provided by the present invention. Concentrations from about 0.001% to about 0.5% of the compound I in the aqueous composition protected thereby could be effectively used. Use of larger concentrations, while feasible, is recommended only for unusual applications. It is preferred to use concentrations from about 0.005% to about 0.2%. These and following percentage concentrations are expressed in weight/volume, based on g/100 ml. of compound of formula I in the pertinent aqueous system susceptible to microbial (bacterial or fungicidal) growth and containing the antimicrobial agent I.

The compounds of formula I may be used inter alia as preservatives for oil-in-water emulsions. A number of oil-in-water emulsions [e.g. cutting oils] are used in industry, for example in the high speed metal working and textile industries, for their cooling, lubricating, antistatic and anticorrosive properties. Unless adequately protected by an effective preservative, such systems are susceptible to bacterial decomposition, producing obnoxious odors and potential health hazards. [Detailed descriptions of these systems, their microbiological problems and difficulties in their preservation can be found in E.O. Bennet. Soap Chem. Specialties 32, 46 (1956); F.W. Fabian et al., Applied Microbiology 1, 199-203 (1953)]. In practicing the invention, the compound may be added by directly dissolving it in the concentrated oil which is then diluted with water to form the water/oil emulsion, or it may be added to the final emulsion either undiluted or dissolved in a solvent such as dimethylformamide. alcohol, acetone, etc. Similar methods known in the art for adding preservatives to such oil-in-water emulsions may also be used. There can be used as little as about 0.005%. Although amounts greater than 0.3% are operable, they are recommended only for unusual applications. It is preferred to use amounts in the range of from about 0.01% to about 0.20%, with amounts in the range of about 0.02% to 0.10% being especially preferred,

The compounds of formula I are effective and could be useful as cosmetic preservatives against the bacteria which spoil cosmetic formulations if they prove to be safe for human use. [Problems encountered in the preservation of cosmetics are described by A. P. Dunnigan, Drug and Cosmetic Industries 103. 43 (1968)]. If the compounds were found to be safe for human use and were used to protect cosmetic formulations, they may be added to the finished cosmetic product directly or dissolved in suitable solvents such as alcohol, acetone, dimethylformamide and the like. Alternatively the compounds may be dissolved in the oils or other raw materials used in the formula and then formulated in the final product. In cosmetic preparations, concentrations as low as 0.01% would be operable. Concentrations greater than 0.30%. while operable, would be recommended only for unusual applications. Concentrations in the range of from about 0.02% to about 0.20% would be preferred with concentrations of about 0.05% to 0.10% being especially preferred.

The following examples illustrate the invention.

I. Manufacture of the antimicrobially active compounds of formula I

Example 1

al. α,α,β-Trichloropropionitrile

Acrylonitrile (150.0g; 2.82 moles) is chlorinated with chlorine gas (>200.2g; >5.64 moles) for approximately 8 hours. The reaction temperature is maintained at 25-30°C by external water cooling. The progress of the reaction is monitored by GLC analysis until essentially a single peak is obtained in the chromatogram. At this point, the flow of chlorine is discontinued and the reaction mixture is degassed by sparging with a vigorous nitrogen flow for one hour. The crude liquid product is distilled to yield 412.0g (92%) of α,α,β-trichloropropionitrile (bp 100°C @ 125mm Hg).

a2. α,α,β-Tribromo (and triiodo)-propionitrile.

Using the procedure outlined in part al, acrylonitrile can be reacted with bromine to yield α,α,β-tribromopropionitrile or with iodine to yield α,α,β-triiodopropionitrile. [See K.C. Pande. U.S.P. 3.659,006, April 25, 1972.]

bl. α,β-Dichloroacrylonitrile.

Into a 500 ml reaction flask is charged α,α,β-trichloropropionitrile (300.0g; 1.89 moles) and quinoline (80.0g; 0.62 mole). The mixture is stirred and heated at reflux (178°C) for 8 hours. (The progress of the reaction is monitored by GLC analysis until essentially a single peak is obtained in the chromatogram.) At this point, the mixture is cooled and the product is isolated by fractional distillation to yield 204. Og (88%) of α,β-dichloroacrylonitrile (bp 70-80°C @ 125mm Hg).

b2. α,β-Dibromoacrylonitrile.

The α,α,β-tribromopropionitrile (263.6g; 0.90 mole) is added to a 500 ml reaction flask and then 2,6-lutidine (146.5g; 1.37 moles) is fed in slowly with stirring at such a rate so as to maintain the reaction temperature at 40°C. The mixture becomes very dark and a precipitate forms. Heat is then applied and the mixture stirred at 45-50°C for 2-3 hours. (Progress of the reaction is monitored by GLC.) The mixture is then cooled to room temperature, dissolved in 500ml of ether, and the ether solution is washed once with water (250ml), twice with 10%-HCl (200ml each) and once with saturated sodium chloride solution (200ml). The washed ether layer is dried over MgSO₄ or NaSO₄, filtered and concentrated on a rotary evaporator to yield 94.2g of red oil. The red oil is distilled to yield 36.9g (19%) of α,β-dibromoacrylonitrile (bp 92-95°C @ 50mm Hg) which is 95% pure by GLC.

c. α-Bromo-β-methylthio-acrylonitrile.

Into a 250 ml reaction flask is added ethanol (50ml) and sodium hydroxide (2.0g; 0.05 mole). The mixture is stirred until the solid is completely dissolved and then methyl mercaptan gas (2.4g; 0.05 mole) is slowly bubbled into the solution. A solution of α,β-dibromoacrylonitrile (10.5g;

0.05 mole) in ethanol (40ml) is then added dropwise over 30 minutes at 25-30°C. The resultant mixture is stirred at room temperature for 16 hours and is then concentrated under vacuum on a rotary evaporator.

The residual material is taken up into water (100ml) and the aqueous mixture is extracted twice with 250 ml portions of ether. The combined ether extracts are washed once with saturated sodium chloride solution (50ml), dried over magnesium sulfate, filtered and concentrated to yield 7.2g of residual oil which is distilled to yield 2.3g of α-bromo-β-methylthio-acrylonitrile (bp 84-94°C @ 1.5mm Hg).

Analysis - Calculated for C₄H₄BrNS : C, 26.97%; H, 2.26%; N. 7.86%. Found: C, 26.72%; H, 2.60%; N, 8.01%. Examples 2-12

Using procedures similar to the one outlined in Example 1 one can prepare other compounds of formula I from the appropriate starting materials. The following table contains a number of representative compounds I. The spectral data (i.e.. NMR, IR, etc.) were consistent with the assigned structures of these compounds.

II. Antimicrobial activity of the compounds of formula I

Example 13

Antibacterial and antifungal activity were evaluated by a 5-fold serial dilution test in agar. In this test, compounds were prepared as 6% solutions in dimethylformamide or ethanol. The 6% solution was then 5-fold serially diluted in test tubes to give the desired concentrations when mixed with agar and poured into sterile Petri dishes. Tryptone glucose extract agar was used for bacterial testing; mildew glucose agar for the fungal testing. The bacterial plates were spot inoculated with 24-hour nutrient broth cultures and incubated at 37°C for 48 hours. The fungal plates were spot inoculated with spore suspensions and incubated at 28°C for seven days. At the end of the incubation periods, all plates were examined for growth. The minimum inhibiting concentration for each organism is expressed in Table II. In the ranges presented, growth is observed only in the lower concentration. The key to Table II is as follows:

Activity Level Growth @ mcg/ml No Growth @ mcg/ml

0 >1920 - -

1 384 1920

2 76 384

3 15 76

4 3 15

5 0 . 6 3

6 0. 12 0.6

7 0.03 0.12

8 _ _ 0.03 Microorganisms Tested

Bacteria Fungi

B₁ Staphylococcus aureus F₁ Aspergillus niger

B₂ Escherichia coli F₂ Aspergillus oryzae

B₃ Pseudomonas aeruginosa F₃ Penicillium piscarium

B₄ Proteus vulgaris F₄ Aureobasidium pullulans

This example illustrates that all the compounds have broad spectrum activity against fungi. Those compounds wherein R is methyl or ethyl are also shown to have broad spectrum activity against bacteria.

III. Applications

Example 14

a. Cutting Oil Emulsions.

The efficacy of the acrylonitriles of formula I as preservatives for cutting oil emulsions was demonstrated by the following test.

Various aliquots of a 6% solution of the test compound in ethanol were added to cutting oil emulsions prepared by diluting Kutwell^® 30 cutting oil concentrate 1 to 30 with water. These samples were inoculated with a culture of

Ps. aeruginosa and incubated at 28°C on a rotary shaker. At weekly intervals, the samples were examined for microorganisms and then reinoculated and incubated. Results are tabulated in Table III.

a. Concentrations tested were 0.98 ppm. 1.95, 3.9, 7.8, 15, 31, 62, 125, 250 and 500 ppm.

This test shows that those derivatives wherein R is methyl or ethyl are highly effective in inhibiting bacterial growth in cutting oil emulsions.

b. Cosmetic compositions.

The efficacy of the acrylonitriles of formula I as preservatives in cosmetic compositions was demonstrated by the following test.

Serial dilutions of the compounds in dimethylformamide were added to a prepared, sterile cosmetic lotion of the following composition:

Ingredients Parts by Weight

Stearic Acid 1.4

Mineral oil 2.3 Arlacel^®-60 (sorbitan monostearate) 0.7 Tween^®-60 (polyoxyethylene sorbitan monostearate) 1.6

Distilled Water 94.0

Total 100.0 parts

Samples of the lotion containing varying levels of the acrylonitrile derivatives were divided into two portions; one portion was inoculated with a spore suspension of A. niger, and the other portion with a 24-hour nutrient broth culture of Ps. aeruginosa. These two organisms are frequently found as contaminants in cosmetic products. The samples were incubated for a 4-week period with weekly examinations for the growth of the organisms. At weekly intervals, the samples were also reinoculated with the test organisms. Presence of fungal growth was determined macroscopically while bacterial contamination was determined by streaking one 4-mm loopful (0.01ml) of the lotion onto the surface of trypticase glucose extract agar (Baltimore Biological Laboratories, Baltimore, MD) containing 0.005% triphenyl tetrazolium chloride and letheen antidote. Results of these tests showing the minimum inhibitory concentration through the 4-week incubation period are tabulated in Table IV and show, once again, that the compounds where R is methyl or ethyl show a broad spectrum activity for the preservation of cosmetic products against the type of fungus and bacterium most likely to cause problems in cosmetics.

Claims

1. A method of controlling microbial growth in an aqueous composition subject to spoilage thereby, which comprises incorporating in said composition an effective amount of a compound of the formula

I

wherein R represents a lower alkyl, aryl, aralkyl, heterocyclyl or thiocarbonyl group and X represents chlorine, bromine or iodine.

2. The method according to claim 1 wherein R represents methyl, ethyl, n-propyl, isopropyl. n-butyl, sec.butyl, isobutyl, tert.butyl, phenyl, p-chlorophenyl, benzyl, 2-thiazolyl, 2-benzothiazolyl, thioacetyl, thiocarbamoyl or dimethylthiocarbamoyl and X is chlorine or bromine.

3. The method according to claim 2 wherein R is methyl or ethyl.

4. The method according to claim 3 wherein the compound I is α-chloro-β-methylthio-acrylonitrile.

5. The method according to claim 3 wherein the compound I is α-chloro-β-ethylthio-acrylonitrile.

6. The method according to claim 3 wherein the compound I is α-bromo-β-methylthio-acrylonitrile.

7. The method according to claim 3 wherein the compound I is α-bromo-β-ethylthio-acrylonitrile.

8. The method according to any preceding claim wherein the compound I is incorporated in the aqueous composition at a concentration of 0.001% to 0.5% weight/volume.

9. The use of a compound of the formula I, as defined in any one of claims 1 to 8, as a microbial agent for controlling microbial growth in an aqueous composition subject to spoilage thereby.

10. A composition containing a compound of the formula I, as defined in claim 1, dissolved in an organic solvent for use in the method according to said claim 1.

11. An aqueous composition protected against spoilage through microbial growth which comprises an effective amount of a compound as defined in any one of claims 1 to 7 as the antimicrobial agent.

12. An aqueous composition according to claim 11 in which the concentration of the antimicrobial agent in the aqueous composition is 0.001% to 0.5% weight/volume.

13. A compound of the formula

I

wherein R represents a lower alkyl, aryl, aralkyl, heterocyclyl or thiocarbonyl group and X represents chlorine , bromine or iodine , except that , when X is bromine, R is other than methyl or phenyl.

14. A compound according to claim 13 wherein R represents methyl, ethyl, n-propyl, isopropyl, n-butyl. sec.butyl, isobutyl, tert.butyl, phenyl, p-chlorophenyl, benzyl, 2-thiazolyl, 2-benzothiazolyl, thioacetyl, thiocarbamoyl or dimethylthiocarbamoyl and X is chlorine or bromine.

15. A compound according to claim 14 wherein R is methyl or ethyl.

16. The compound according to claim 15 which is α-chloro-β-methylthio-acrylonitrile.

17. The compound according to claim 15 which is α-chloro-β-ethylthio-acrylonitrile.

18. The compound according to claim 15 which is α-bromo-β-ethylthio-acrylonitrile.

19 . A process f or produc ing a compound of the f ormula

' I

wherein R represents a lower alkyl, aryl, aralkyl, heterocyclyl or thiocarbonyl group and X represents chlorine, bromine or iodine, except that when X is bromine, R is other than methyl or phenyl, comprising subjecting an appropriate α,β-dihaloacrylonitrile of the formula

IV

to a nucleophilic-type displacement of the halogen atom X attached to the β-carbon atom using a sulfur anion RS^Θ derived from the appropriate mercaptan RSH.